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A Deep Dive on Autophagy & Spermidine


Spermidine is one of the autophagy inducers that has gotten little attention in the public domain while being intensively researched by world-renowned experts. For normal development and function of tissues, spermidine is essential. It is proved to reverse all 12 hallmarks of aging.

Our bodies are made up of more than 100 trillion cells. These cells have a remarkable capacity for self-repair, allowing them to do so efficiently. Whenever a certain number of cells die, at the same time, another set of cells is generated, and the cycle goes on.

But this procedure does not always operate smoothly. Misfolded proteins, damaged cell organelles, and “cell trash” can collect and become stuck in the body over time. But the good news is that our body has built a recycling mechanism to guarantee that this waste does not interfere with the body’s operations. This process is known as autophagy.

What Is Autophagy?

The literal definition of autophagy is “self-eating.” But it is the cellular process through which unwanted materials (such as dead or injured parts of the cell, bacteria, and chemicals) are removed. The cellular organelle termed a lysosome receives the waste products during this sorting and cleaning process so they can be degraded and recycled.


The theory of autophagy and how important it is are fairly new. Yoshinori Ohsumi was awarded the 2016 Nobel Prize in Physiology or Medicine for discovering how autophagy works.

Enhancing autophagy, which has been observed in extraordinarily healthy centenarian adults, looks to be a crucial focus for living a better, longer life. Although genes are involved in autophagy, environmental factors such as diet, lifestyle, and nutritional supplements can also majorly impact gene expression.

Effects of Autophagy Dysfunction

Prior to explaining ways to increase autophagy, it’s important to note the impacts of malfunctioning autophagy.

  • Symptoms of an accelerated rate of biological aging include an increase in oxidative damage, a loss of control in protein synthesis and degradation, a decline in mitochondrial function, and a decline in immune function. Since the brain is the most metabolically active tissue in the body, it is highly susceptible to these effects.
  • Age-related reduction in autophagy also contributes to sarcopenia, the gradual loss of muscle mass and strength associated with aging.
  • Recent researches also suggest that coronavirus can also induce autophagy, according to an article published in Microbial Cell.

More than 40 genes contribute to autophagy. However, the autophagy mechanisms linked to human longevity are mostly determined by the overexpression of a key autophagy gene (ATG5).

If your cells are already weak and unhealthy as you get older, it’s only a matter of time until the rest of your body follows suit. To live a long and healthy life, autophagy must function normally, and this is a hypothesis that has been supported by scientific research.

Triggering Autophagy

Studies have suggested many mechanisms through which we can induce autophagy in humans,

  • Fasting: Reducing calorie intake, or fasting, is the quickest approach to examine autophagy at work. Fasting for more than 24 hours has proven to be an effective research method. Whereas intermittent fasting is the most widely adopted approach.
  • Exercise is a great way to break down tissue by inducing positive stress. The damaged tissue heals and grows back stronger than before. Exercising the muscle, liver, pancreas, and adipose tissue can all trigger autophagy, which aids in metabolic balance.

Pregnant women, nursing mothers, and small children should not follow a calorie-restricted diet for long periods. What if, however, there were a method to induce autophagy and receive its advantages while avoiding some of these commitments?

New evidence reveals that we may still reap the health advantages of autophagy by increasing our intake of spermidine through diet or anti-aging supplements.

Why? As spermidine acts as a “caloric restriction analogue.”

Spermidine & Autophagy

Spermidine is a polyamine with simply a compound with more than two amino groups. It is endogenous, meaning that we can produce it in our bodies on our own. It can be created by tissue or any bacteria in the gut. It has been proven as a prerequisite for growth along with many other polyamines.

About a decade ago, an Austrian research group at the University of Graz found that spermidine might initiate autophagy.

The way spermidine induces autophagy is via inhibiting acetyltransferases. While this reduces the acetyl levels in the cells, it also inhibits the mTORC1 pathways (an increase of this can reduce lifespan), which causes the activation of AMPK pathway. By inducing autophagy, spermidine can affect a lot of different aging pathways. Since this groundbreaking finding, around one hundred research groups have studied this substance for its potential medical applications.

spermidine and autophagy.

This similar mechanism underlies the beneficial effects of calorie restriction (e.g., intermittent fasting) on health and longevity.

Numerous research studies demonstrate that autophagy declines with aging. It is a condition that is easily reversible with fasting or spermidine supplementation. (1)(2)(3)(4)

As of late, its efficacy has been measured and shown to be on a level with that of rapamycin, an immunosuppressant with protective and autophagy-stimulating effects licensed for use in the United States by the Food and Drug Administration.

For Lifespan

In 2009, Spermidine plus two other chemicals, Resveratrol and Rapamycin, had been shown to cause lifespan in yeast, making the first discovery of spermidine an important scientific milestone

Researchers at the University of Innsbruck tracked their subjects for 20 years. They discovered that those who consumed more foods high in the amino acid spermidine had a reduced risk of dying and lived an extra five years longer than those who did not.

The effects of spermidine on lifespan were investigated in a recent study that involved 29 scientists. The study found that spermidine treatment prolonged the lives of yeast, flies, worms, and human immune cells. They also discovered that polyamine-mediated prevention of necrosis and longer lifespan rely heavily on the accelerated autophagy produced by spermidine intake. The study confirms that polyamine decline has been linked to aging on several occasions. (1)

Two further investigations have shown that spermidine supplements diminish aging markers in animals.

Human Clinical Trials

Age-related Cognitive decline: The new clinical study aimed to determine if spermidine supplementation improves memory and whether or not it protects against age-related cognitive decline. A daily dose of 0.9 milligrams was used for 3 years. Ultimately, the study’s authors determined that spermidine supplementation had no effect on memory or biomarkers. This was due to the low dosage of spermidine for the trial.

Overall Improvement In health: A report for the first time of spermidine usage as a nutritional supplement has been linked to a human overall reduction in cardiovascular and cancer-related health rates. Food frequency questionnaires were used in research to determine an individual’s polyamine (including spermidine) intake through diet. (1) After accounting for potentially confounding factors like caloric intake, age, sex, BMI, diabetes, hypertension, physical activity, smoking, and alcohol consumption, those subjects who consumed more spermidine in their diet had a lower risk of dying from any cause and cardiovascular disease specifically.

Reduced Death rates: A review article based on a study of the diets of 24,000 US adults from 2003–2014 is one of the most current publications on the effects of spermidine in humans. The study concluded that there were statistically significant associations between spermidine consumption and death rates from cardiovascular disease and overall causes of death.

Hair growth: Human hair growth and resistance were boosted by spermidine in a 90-day trial with spermidine 0.1–1 µM application.

Ongoing Trials:

  • A new study on the autophagy of spermidine is under trial, and 6mg/ spermidine is used to evaluate the efficacy.
  • Another ongoing human study aims to use established tests to learn whether or not taking a spermidine supplement daily is safe for older adults after receiving a booster dose of the SARS-CoV-2 vaccination.

How To Measure Autophagy?

It can be difficult to assess autophagy at home, particularly when you are not a skilled and knowledgeable scientist or researcher. But one can track autophagy by looking at the structures that are involved in autophagy or by measuring how much proteins and organelles break down when autophagy and lysosomes are involved.

Scientists all over the world are looking for “biomarkers” of autophagy so they can track its progress. However, we already know that there are at least some physiological indications that are linked:

  • Fasting: Possible indicator of autophagy is fasting. It shows that even if you are eating or not, the body still has enough resources to get its nutrition.
  • Reduced Hunger: A decrease in hunger is a hallmark of autophagy. We can attribute this to fluctuating glucagon and insulin levels. Glucagon helps regulate sugar levels and has been shown to decrease hunger.
  • Weight Loss: Loss of body fat is a possible result of autophagy since it promotes fat burning.
  • Low Blood Sugars: When your blood sugar level is dipped, your body will produce more cortisol, growth hormones, and ketones. This can make it possible to start the process of autophagy.
  • Ketones in the Body: Your body produces more ketones in response to decreased blood sugar from fatty acids. Ketone levels in the blood, breath, and urine may be measured with simple meters and strips, allowing one to quickly and easily verify if autophagy is occurring.


As previously established, autophagy is notoriously hard to quantify outside a controlled laboratory setting. These methods can be used to access that we can measure somehow.

What Dosage is Best?

  • In a trial, 3.4 mg of spermidine was set for an average person who weighs 70 kg.
  • Dr. Sinclair, an internationally recognized expert on longevity, said in a podcast interview that he begins each day with 1 milligram (mg) of spermidine.
  • A dosage of 1.2 mg of spermidine was studied with mice and older people responded well to a spermidine-rich plant extract.
  • Spermidine doses up to 6 mg/day were considered non-hazardous.

To aid cellular wellness without the unpleasant side effects of severe fasting practices or to promote the beneficial effects of autophagy, spermidine supplementation can be used. The advantages of spermidine and polyamine supplementation, which start to show up in the cells on day one but increase with time, are well-documented.

To give your cells time to adapt to greater spermidine levels and the heightened autophagy advantages, It is advised to start with a cycle of at least 60 days.


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